Ultrasonically enhanced substance delivery method

ABSTRACT

A method for enhancing delivery of at least one substance through a surface of and into a subject. The method includes situating the substance adjacent to the surface of the subject. The method includes placing at least one ultrasonic signal emitting device adjacent to the substance such and to the subject. And, applying at least one alternating ultrasonic signal to the substance using the ultrasonic signal emitting device so as to effect movement of at least a portion of the substance through the surface and into the subject.

RELATED APPLICATIONS

[0001] This application claims priority of each of: U.S. patentapplication Ser. No. 60/300,343, filed Jun. 22, 2001 and entitled“ULTRASONIC TRANSDUCER APPARATUS AND METHOD OF USE SUITABLE FORULTRASONIC DRUG DELIVERY VIA A SYSTEM WHICH IS PORTABLE AND WEARABLE BYA SUBJECT”; U.S. patent application Ser. No. 60/300,292, filed Jun. 22,2001 and entitled “TRANSDERMAL PATCH FOR USE IN ULTRASONIC DRUG DELIVERYAPPLICATIONS”; and, U.S. patent application Ser. No. 60/227,359, filedAug. 24, 2000, entitled “TRANSDERMAL DRUG DELIVERY SYSTEM UTILIZING AWEARABLE, PORTABLE SONIC APPLICATOR”, the entire disclosures of whichare each respectively hereby incorporated by reference herein as ifbeing set forth in their respective entireties.

FIELD OF THE INVENTION

[0002] The present invention relates generally to substance deliverymethods, and more particularly to methods suitable for enhancingtransdermal substance delivery.

BACKGROUND OF THE INVENTION

[0003] Transdermal substance delivery systems, such as drug deliverysystems, may employ a medicated device or patch affixed to an exposedsurface of a patient's skin. The patch allows a substance, such as amedicinal compound contained within the patch, to be absorbed into theskin layers and finally into the patient's blood stream. Transdermaldrug delivery often avoids pain associated with drug injections andintravenous drug administration. Transdermal drug delivery may also beused to avoid gastrointestinal metabolism of administered drugs, reduceelimination of drugs by the liver, and for providing a sustained releaseof an administrated drug. Transdermal drug delivery may also enhancepatient compliance with a drug regimen because of the relative ease ofadministration and the sustained release of the drug.

[0004] However, it is believed that several medicinal compounds are notsuitable for conventional transdermal drug delivery, since they areabsorbed through the skin with difficulty, due to the molecular size ofthe drug or other bioadhesive properties of the drug, for example. Inthese cases, when transdermal drug delivery is attempted, the drug maybe found to merely pool on the outer surface of the skin and notpermeate into the blood stream. Once such example is insulin, which hasbeen found difficult to administer by means of conventional transdermaldrug delivery.

[0005] Further, some critically needed medications are presentlyadministered either by injection or oral dosage forms. In particular,chemotherapeutic agents are often administered in increased dosagesbecause of their need to survive degradation in the gastrointestinaltract, for example. Also, many critical treatments for AIDS require acocktail of drugs taken orally in solid dosage forms, several times aday, to be effective. These medications are not believed suitable forconventional transdermal drug delivery use because of the extensivedosing requirement, and the inability of the drug molecule to remainstable in a transdermal form, for example. Moreover, the unsuitabilityfor conventional transdermal to skin transfer of the drug leads to lowbioabsorbance of the drug across the skin layers.

[0006] Generally, conventional transdermal drug delivery methods havebeen found suitable only for low molecular weight medications such asnitroglycerin (for alleviating angina), nicotine (for smoking cessationregimens), and estradiol (for estrogen replacement in post-menopausalwomen). Larger molecular medications such as insulin (a polypeptide forthe treatment of diabetes), erythropoietin (used to treat severe anemia)and gamma-interferon (used to boost the immune system's cancer fightingability) are all compounds not normally effective when used withconventional transdermal drug delivery methods, for example.

[0007] Other methods of increasing the permeability of skin to drugshave been described, such as iontophoresis. Iontophoresis involves theapplication of an external electric field and topical delivery of anionized form of drug or unionized drug carried with the water fluxassociated with ion transport (electro-osmosis). While permeationenhancement with iontophoresis has been effective, control of drugdelivery and irreversible skin damage are problems that may beassociated with the technique.

[0008] Ultrasound has also been suggested to enhance permeability of theskin and synthetic membranes to drugs and other molecules. Ultrasoundhas been generally defined as mechanical pressure waves with frequenciesabove 20 kHz. Ultrasound signals can be generated by vibrating apiezoelectric crystal or other electromechanical element, such asthrough passing an alternating current through the material. The use ofultrasound to increase the permeability of the skin to drug moleculeshas been termed sonophoresis or phonophoresis.

[0009] However, while the use of ultrasound for drug delivery has beengenerally suggested, results have been largely disappointing in thatenhancement of permeability has been relatively low. Further, it isbelieved that there is no consensus on the efficacy of ultrasound forincreasing drug flux across the skin. While some studies report thesuccess of sonophoresis, others have obtained negative results.

[0010] Many conventional ultrasonic transdermal delivery systemsenvision a typical ultrasonic wand or sonicator as an ultrasonicapplicator, not taking into account the power utilization of thetransducer and the size of the device.

[0011] Since ultrasound is rapidly attenuated in air, a coupling agent,preferably one having a low realizable absorption coefficient that isnon-staining, non-irritating, and slow drying, may be needed toefficiently transfer the ultrasonic energy from the ultrasoundtransducer into the skin. When a chemical enhancer fluid oranti-irritant, or both, are employed, they may function as the couplingagent. For example, glycerin used as an anti-irritant may also functionas a coupling agent. If needed, additional components may be added tothe enhancer fluid to increase the efficiency of ultrasonictransduction.

[0012] In general, ultrasound exposure times for permeation throughhuman skin have conventionally been 10 minutes to 24 hours. The depth ofpenetration of ultrasonic energy into living soft tissue is inverselyproportional to the frequency, thus high frequencies have been suggestedto improve drug penetration through the skin by concentrating the effectin the outermost skin layer, the stratum corneum.

[0013] Although it has been acknowledged that enhancing permeability ofthe skin may make it possible to transport molecules into the body fortherapeutic purposes, portable programmable devices and methods have notbeen disclosed.

[0014] In view of the foregoing problems and/or deficiencies, thedevelopment of a transducer device for safely enhancing the permeabilityof the skin for noninvasive drug delivery in a more rapid time framewould be a significant advancement in the art.

SUMMARY OF THE PRESENT INVENTION

[0015] A method for enhancing delivery of at least one substance througha surface of and into a subject, the method including: situating thesubstance adjacent to the surface of the subject; placing at least oneultrasonic signal emitting device adjacent to the substance such and tothe subject; and, applying at least one alternating ultrasonic signal tothe substance using the ultrasonic signal emitting device so as toeffect movement of at least a portion of the substance through thesurface and into the subject.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The present invention will be more readily understood inconnection with the non-limiting, attached figures, wherein:

[0017]FIG. 1 is an artist's depiction of an ultrasonic drug deliveryapparatus, worn by a patient upon the arm.

[0018]FIG. 2 is an artist's depiction of an ultrasonic drug deliveryapparatus, worn by a patient upon the abdomen.

[0019]FIG. 3 is an illustration of the structure of human skin.

[0020]FIG. 4A illustrates a cross section view of an embodiment of thetransducer element of the present invention, said transducer elementbeing a “cymbal” type transducer design.

[0021]FIG. 4B illustrates the fabrication steps to produce a “cymbal”type transducer element.

[0022]FIG. 4C illustrates a cross section view of transducer element astacked “cymbal” type transducer designed to provide higher ultrasonicefficiency intensity and power output.

[0023]FIG. 5A illustrates dimensional characteristics of an embodimentof the present invention, including use of a polymer potting used as aresonance compatible coupling agent coating over the surface of thetransducer element.

[0024]FIG. 5B illustrates the small dimensions obtained in thefabrication of a “cymbal” type transducer element.

[0025]FIG. 6. Illustrates an array of transducers used to enhance sonicefficiency and to provide multiple delivery sites to the skin.

[0026]FIG. 7. depicts the use of an alternating waveform, a conversionfrom sawtooth to square wave.

[0027]FIG. 8A shows a scan using a HPLC of insulin, Humilin Regular,supplied by Eli Lilly Co., where no ultrasound was applied.

[0028]FIG. 8B shows a scan using a HPLC of insulin, Humilin Regular,supplied by Eli Lilly Co., after the sample was treated with lowfrequency and low intensity ultrasound continuously over a eight hourperiod.

[0029]FIG. 9 shows the results of glucose analysis in the blood ofsubject rats, where the transducer array was used in a test for thetransdermal delivery of insulin.

[0030]FIG. 10 illustrates a method according to an aspect of the presentinvention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] It is to be understood that the figures and descriptions of thepresent invention have been simplified to illustrate elements that arerelevant for a clear understanding of the present invention, whileeliminating, for purposes of clarity, many other elements found inconventional ultrasonic substance delivery systems. Those of ordinaryskill in the art will recognize that other elements are desirable and/orrequired in order to implement the present invention. However, becausesuch elements are well known in the art, and because they do notfacilitate a better understanding of the present invention, a discussionof such elements is not provided herein.

[0032] Reference is hereby made to commonly assigned and copending U.S.patent application Ser. No. not yet assigned, entitled “ULTRASONICALLYENHANCED SUBSTANCE DELIVERY SYSTEM AND DEVICE”, filed on even dateherewith, the entire disclosure of which is hereby incorporated byreference herein.

[0033] According to an aspect of the present invention, at least oneultrasonic transducer device may be provided for enhancing transdermalsubstance delivery by the use of ultrasound, especially of largerpharmaceutically active compounds for example. The terms “drug” or“pharmaceutically active compound” as used herein should be understoodto be used in a non-limiting manner and for purposes of explanationonly, as the present invention is suitable for delivering manysubstances including drugs and pharmaceutically active compounds notonly transdermally, but transmucosally as well for example. Thetransducer device may be small in size, battery powered, highlyefficient and able to generate an ultrasonic transmission suitable foreffecting the transmission of a pharmaceutical compound from atransdermal patch.

[0034] An ultrasonic transducer device may be placed it directly incontact with a transdermal delivery device or patch for the purpose ofboth enhancing and controlling the delivery of medications containedwithin the patch into and through the skin layer of a target patient.The transducer device may be placed directly within a drug-containingpatch or worn over the patch, and held in place by adhesive strips orbody affixing straps, for example. The transdermal patch may contain aparticular medication or cocktail of medications for treatment ofdisease or relief of pain.

[0035] According to an aspect of the invention, the transducer device issuitable for applying ultrasound to a transdermal patch for controllingtransdermal and/or transmucosal flux rates of drugs and other moleculesinto the body and the bloodstream. A Class V flextensional cymbaltransducer and transducer array may be used to deliver low frequencyultrasound in a portable device at high efficiency for transdermal drugdelivery and therapeutic applications.

[0036] According to an aspect of the present invention, transport ofdrug molecules may be accomplished using pathways associated with hairfollicles and skin pores. A method for non-invasive delivery ofbiologically active molecules through the skin and mucosal membranesusing ultrasound may be accomplished.

[0037] According to an aspect of the invention, several areas of theskin, i.e. transport sites, may be treated simultaneously orsequentially using multiple transducers configured into one or moretransducer arrays, for example. Various ultrasound frequencies,intensities, amplitudes and/or phase modulations may be used to controlthe magnitude of the transdermal flux to achieve a therapeutic ornutritional level. According to an aspect of the invention, theprogrammability and flux control may allow for optimized therapeuticdelivery for an individual patient (examples may include patients thatare at different stages of the disease, elderly patients, young,juvenile, or according to gender). The optimization may be substancespecific, for example. The molecular structure of each biologicallyactive molecule is different and responds differently to ultrasound.Control of the frequency, intensity, concentration, timing of delivery,drug regimen can optimize delivery of each drug type.

[0038] According to an aspect of the invention, the transducer or arrayof transducers can be built into the patch or slid into the patch, forexample. According to an aspect of the invention, the transducer devicecan be used for insulin delivery.

[0039] According to an aspect of the invention, phase modulation,alternating waveforms and/or frequency modulation can be used to enhanceultrasonic transdermal substance transport and increase a rate ofsubstance delivery to a subject, e.g. human, other mammal, animal or anyother object of which substance delivery through a surface thereof maybe ultrasonically enhanced. The ultrasound may be combined withiontophoresis, electroporation, depilatories, and/or chemical enhancerssuch as surfactants to facilitate transdermal permeation.

[0040] According to an aspect of the present invention, acousticalenergy delivered by a portable, self-powered, programmable ultrasonictransducer placed over a substance containing patch causes the substanceto be transferred across the surface, e.g. skin, barrier.

[0041] According to an aspect of the present invention, a portableprogrammable ultrasonic device, which may be worn by a patient over atransdermal drug delivery patch may be provided for the purpose ofenhancing the penetration of substances such as medicinal compounds ordrugs contained within the transdermal patch, through the skin into thepatient's blood stream. Further, the portable ultrasonic applicator maybe programmed to apply acoustical energy at different times and therebycause the delivery of a varying quantity of the medicinal compound overtime. The portable ultrasonic applicator may be programmed to deliver amedicinal compound to the patient continuously (sustained release)and/or intermittently (pulsed release), whichever may be deemed moreappropriate to a drug maintenance and treatment regimen for a particularpatient.

[0042] According to an aspect of the present invention a device, whichmay be worn by the patient, is programmed to deliver an ultrasonicsignal through a transdermal patch according to a timing circuit.Transducers used may be sufficiently small and compact to allow forconvenient portability and wearability. The transducers may be poweredby a battery, which may also be portable and worn by the patient.

[0043] According to an aspect of the present invention, some parametersof applied ultrasound that can be changed to improve or controlpenetration include frequency, intensity, and time of exposure. Any orall three of these parameters may be modulated simultaneously in acomplex fashion to increase the effect or efficiency of the ultrasoundas it relates to enhancing the transdermal molecular flux rate eitherinto or out of the human body.

[0044] According to an aspect of the present invention, a microprocessorcoupled with an EEPROM, a timer unit, and a waveform generator may beused to provide for programmability and time-dependent operation of thetransdermal drug delivery system. As is well understood in the pertinentarts, this is often termed a “control unit”. Of course, alternativedevices for effecting analogous controls for implementing the presentinvention may be provided. Programmability may include the ability tocontrol a quantity of drug delivered, the time interval and duration ofdrug delivery, and the frequency and intensity of the applied controlwaveforms to the transducer. Both programmable and manual operation maybe utilized. The waveform generator may be programmed to provide a sine,a square or a sawtooth waveform used to control the transducer. Ofcourse, other waveforms may also be utilized. The frequency of thecontrolled waveforms may be from about 20 k Hz to about 100 k Hz. Thewaveforms may be sequentially interleaved to provide different waveformsfor different durations and/or different amplitudes. Multiple waveformsmay also be generated simultaneously.

[0045] A method of superpositioning or summing of waveforms may also beprovided to combine, for example, square and sawtooth waveform at thetransducer inputs. Waveform control outputs may be applied to aplurality of transducers simultaneously or may be divided and timephased so as to permit sequential operation of different transducerelements. The timing generator and EEPROM may serve to store drugspecific delivery scenarios in memory. For example, a basal timingsequence and a bolus timing sequence may be programmed, stored, and thenretrieved and executed; thereby controlling the transducer or transducerarray in a specific drug delivery operation.

[0046] A pulsed or continuous mode of operation may also be selected. Inaddition, an electric signal, which may be directed through the skin ofthe subject at any time during the drug delivery sequence, may also beprovided. The electric signal may be programmed to be anywhere in therange of 1 to 20 Volts, for example. The electronic control unit may bebattery operated for portability and ease of use.

[0047] According to an aspect of the present invention, multipletransducers configured in an array may be used so as to change the areaof the skin used for drug absorption, i.e. the transport sites.

[0048] According to an aspect of the present invention, transdermaldelivery of pharmaceutical agents using ultrasonic stimuli may beimproved using variable frequencies and intensities in order to delivertherapeutic quantities of drugs to patients. Variables such as fatcontent and mass of a particular patient's tissue, through which thedrug will be delivered, may vary the frequency and intensityrequirements used to obtain an effective dosing regimen.

[0049] According to an aspect of the present invention, encapsulation ofsubstances and/or various compounds to be delivered may increase thepermeability thereof and allow for slow time release of medication, forexample. According to an aspect of the present invention, excipients maybe used to improve transport through the stratum corneum and absorptioninto the blood stream. Several substances, such as drugs, may be appliedusing this method for local application of medication.

[0050] Referring now to FIG. 1 there is shown a wearable, non-invasive,ultrasonic-transdermal drug delivery system 10, including ultrasonicapplicator 1 placed directly over a transdermal delivery device or patch2. The applicator 1 and/or patch 2 may be attached to an exterior of apatient's skin 3 by means of adhesive and/or a strap 4, which holds theultrasonic applicator 1 and patch 2 in place. Power for the ultrasonicapplicator 1 is provided by power cells 12, for example which may berechargeable, and may be located within the strap 4 itself, for example.Alternatively the power supply may be contained within the ultrasonicapplicator device 1 itself or provided by any conventional externalsource.

[0051]FIG. 1 illustrates applicator 1, patch 2 and band 4 on the arm ofthe patient. It should be recognized however that a system according tothe present invention may be placed over the patient's chest (as in thecase of nitroglycerin drug delivery for example) abdomen (abdomen 6 asseen in FIG. 2), or any other suitable part of the patient's body asdetermined by the medical personnel administrating the drug treatmentregimen. Other body placements include, but are not limited to, theneck, back and legs, for example. FIG. 2 shows ultrasonic applicator 1affixed directly over the transdermal patch 2 and held onto bare skin 3of a patient, wherein the transducers 4 are placed directly in contactwith the transdermal patch 2, in this instance affixed to the patientsabdomen 3.

[0052]FIG. 3 illustrates the structure of human skin. Essentially thereare three pathways through the skin into the bloodstream: 1) breachingthe Stratum Corneum; 2) passing a pharmaceutical agent through pores inthe skin; and, 3) passing a pharmaceutical agent through the skin byfollowing the hair follicle to the hair root, and from there into thevascular network located at the base of the hair root.

[0053] Referring to FIG. 10 , according to an aspect of the presentinvention, a substance may be delivered through a surface of and into aliving subject 10 by affixing at least one ultrasonic signal emittingdevice adjacent to said at least one substance and to said subject 100.At least one ultrasonic signal may be applied 200 to the at leastsubstance using the ultrasonic signal emitting device so as to effectmovement of at least a portion of the substance through the surface andinto the subject. The at least one applied ultrasonic signal may includeat least a square waveform portion and a sawtooth waveform portion.

[0054] According to an aspect of the present invention, transdermal drugdelivery may be provided by utilizing drug pathways associated with thepore and the hair follicle system on the patient's skin. Moreparticularly, according to an aspect of the present invention, theultrasonic frequency, intensity level and/or waveform dynamics ofdelivered ultrasound are adjusted to exploit drug delivery through thehair follicle pathway primarily and through the pores in the skinssurface secondarily, but not directly through the stratum corneum, as itis believed the amount of energy needed for piercing the stratum corneummay be excessive and potentially damaging to fatty tissue.

[0055] According to an aspect of the present invention, through the useof alternating waveforms, the amount of energy transmitted to thesurface of the skin may be minimized while also providing a pressurewave effect upon the skin, enhancing drug delivery through the hairfollicle and pore system. Referring to FIG. 7, according to an aspect ofthe invention, an ultrasonic waveform dependent upon a sawtooth tosquare wave alternation is utilized. The amplitude of and intensity ofsuch wave shaping aids in both the homogenization of a drug containedwithin the transdermal patch and miniaturizing a beadlet size of theactive pharmaceutical substance within the patch, and in drug transportthrough the skin. The short, peaked portion of the ultrasonic waveformresulting from a sawtooth shaped input helps with drug homogenization,without imparting destructive frequencies and cavitation to the drugsubstance. Upon conversion to the square waveform, the ultrasonictransmission acts to massage and open the fatty tissue surrounding thehair follicle and pores. Drugs permeating from the transdermal patch arepreferably in monomer form and/or reduced in droplet size, belowapproximately 50 Angstroms, making them more suitable in dimension topass through the skin. The square waveform may help to “push” the drugthrough the pores and alongside the hair follicles, where the drug makesits way to the hair root, and directly into the bloodstream at thevascular network.

[0056] According to an aspect of the present invention, the frequencyand intensity of that portion of the ultrasonic signal resulting fromthe square waveform portion and impinging a transport site may be about20 kHz at about 125 mW/sq. cm to about 225 mW/sq. cm, while thefrequency and intensity of the portion of the ultrasonic signalresulting from the sawtooth waveform portion is about 20 kHz at about125 mW/sq. cm to about 225 mW/sq. cm. Further, each waveform can beprovided for about 100 milliseconds, before transitioning to the other,for example.

[0057] To ultrasonically enhance or promote transdermal delivery 20 ofsubstances such as drugs, transdermal patch 2 may be designed to work inconjunction with ultrasonic applicator 1. Reference is hereby made tocommonly assigned and copending U.S. patent application Ser. No. not yetassigned, entitled “SUBSTANCE DELIVERY SYSTEM”, filed on even dateherewith, the entire disclosure of which is hereby incorporated byreference herein. In summary, this application describes a patchsuitable for use in combination with the present invention, and thereader is advised to study this application for a more detailed analysisthere-regarding. In particular, the contact between the applicator andthe patch preferably promotes efficient acoustic energy transmission.The selection of the materials and adhesives is important to maintainthe intensity and power output of the ultrasonic transmission from thetransducers through the transdermal patch. It is believed that insulin,one of many active pharmaceutical substances being suitable for enhanceddrug delivery via the present invention, has a large molecule size, andforms hexamers generally over about 50 Angstroms, making it difficult topermeate through the pores of the skin. Further, insulin molecules tendto agglomerate when stored and as a result zinc. Insulin stored withinthe patch may therefore tend to agglomerate into even larger drug clumpsizes, further reducing skin transport potential.

[0058] To help alleviate this problem and to keep the drug at a sizesufficiently small enough for skin transport, the ultrasonic signal maybe altered, from time to time, using a sawtooth to a square waveformstimuli. It should be understood however that other varying waveformshaving alternating average imparted powers for example can of course beutilized. Nonetheless, for purposes of illustration FIG. 7 shows analternating waveform, wherein a sawtooth waveform (of relatively lowaverage power) is used to drive one or more transducers to homogenize adrug within a patch, leading to increased skin transport as theultrasonic waveform stimuli switches to a square wave shape (ofrelatively high average power). As will be readily understood by thosepossessing an ordinary level of skill in the pertinent arts, thesawtooth waveform portion leads to a short period of high energy, with ashort duration of pressure amplitude, leading to a vibration effect withthe targeted pharmaceutical substance. This vibration is with a low heatpotential and may have the effect of mixing or homogenizing the drugwithin the patch. Thus, smaller beadlet sizes may be made possible bythe sawtooth waveform portion.

[0059] Conventional transdermal substance delivery pathways through thestratum corneum may enable initial quantities of a drug to permeatethrough the skin, but as longer periods of ultrasound are applied to thesame location on the skin the delivery rate may drop off or be reducedto zero. This may imply that ultrasound applied to same site at theskin's surface should not be continued for lengthy periods of time. Itis believed that one or more attempts in the previous art to breach thestratum corneum failed over time because cavitation eventuallyover-heated the fatty tissue contained within the epidermis, resultingin a changed density of the fatty composites within this skin layer. Anincrease in such density may retard further drug permeation through theskin.

[0060]FIG. 4A illustrates the design of a cymbal type of ultrasonictransducer 40 which can be utilized according to an aspect of thepresent invention. Cymbal transducer 40 includes piezoelectric disc 41,such as PZT4 available from Piezokinetics Corp., Bellefonte, Pa.,connected to two metal caps 42, which may be composed of titanium foilfor example. FIG. 4A illustrates that there is a hollow air space 43between the piezoelectric disc 41 and the end caps 42. The end caps 42are connected to the piezoelectric disc 41 by a non-electricallyconductive adhesive 44 to form a bonded layered construction to thetransducer 40. Cymbal transducers offers a thin, compact structure wellsuited for a portable ultrasonic drug delivery apparatus. Additionallysuch a transducer offers sufficient efficiency for the conversion ofelectric power to acoustically radiated power. Such a transducer designalso provides potential to be battery powered, and is small andlightweight.

[0061]FIG. 4C illustrates a stacked cymbal type of ultrasonic transducer40 which can be utilized according to an aspect of the presentinvention. In a stacked transducer construction greater intensity ofultrasonic signals can be utilized. U.S. Pat. No. 5,729,077, issued Mar.17, 1998, entitled “METAL-ELECTROACTIVE CERAMIC COMPOSITE TRANSDUCER”(Newnham et al.), the entire disclosure of which is incorporated byreference herein, discloses the use of stacked transducers, essentiallytransducers fitted atop each other, to increase ultrasonic intensitieswhile maintaining a given frequency level. A stacked transducerconstruction may be used to increase intensity while improving the powerutilization of the transducer system.

[0062]FIG. 5A illustrates the sizing of the transducers which may beused, and which can be about 0.5″ inches in diameter. The use of such arelatively small size transducer enables the transducers to fit withinthe dimensions of a transdermal patch, for example. In addition thesmall size enables a lower weight potential for the transducers, againaiding in the portability of the invention. The transducer element 50 isa cymbal type construction attached to a power cable 51. The transducerelement 50 is coated in a polymer housing 52, composed of a polyurethanematerial suitable for castings, coatings, and/or adhesives, such as aUralite resin for example, which is used to avoid short circuits betweenthe two metallic caps 42 (See, FIG. 4A) and provides acoustic couplingfor the sonic transmission.

[0063]FIG. 5B illustrates possible dimensions using a “cymbal” typetransducer element. The cymbal type transducer design offers severaladvantages to the present invention, including, but not limited to:compact structure, with small surface area; high acoustic pressure andhigh acoustic intensity at low resonance frequency; high efficiency,making the system require less driving power; the use of low resonancefrequency to avoid a high cavitation threshold, i.e., the intensityrequired to generate air bubbles within the stratum corneum of thepatient's skin tissue. The cavitation threshold is inverselyproportional to the frequency applied so the choice of a low resonancefrequency of the transducer permits a lower acoustical pressure appliedto the surface of the skin and transdermal drug delivery is effected.

[0064] For a more thorough discussion regarding cymbal transducers ingeneral, the reader is referred to the following U.S. Pat. No.4,999,819, issued Mar. 12, 1991, entitled “TRANSFORMED STRESS DIRECTIONACOUSTIC TRANSDUCER” (Newnham, et al), U.S. Pat. No. 5,276,657, issuedJan. 4, 1994, entitled “METAL-ELECTROACTIVE CERAMIC COMPOSITE ACTUATORS”(Newnham, et al) and the aforementioned U.S. Pat. No. 5,729,077(Newnham, et al), the entire disclosures of which are herebyrespectively incorporated by reference as if being set forth in theirrespective entireties herein.

[0065]FIG. 6 shows an array 60 including more than one-cymbal element 61arranged in a pattern (or array) onto a substructure or encased within apolymer housing 62. The array can take any suitable form, such as a 2×2array or a 3×3 array, for example. The cymbal elements 61 may beconnected in parallel by a series of electrical connections 63. Thearray 60 may be sealed in polymer potting material 62, again composed ofUralite for example. Such an array enables a portable, battery powered,ultrasonic transmission with sufficient power to effect drug deliveryvia a transdermal patch.

[0066] According to an aspect of the present invention, the sonicapplicator 1, as shown in FIG. 6, can transmit ultrasonic signalsthrough multiple transducers, that is at multiple transport sites. Theactivation of one or more elements of the transducer array may besequenced from transducer element to transducer element, optionallyusing different waveforms, frequency, amplitudes, and duty cyclesbetween each transducer element, for example. It is believed that thisserves to advantageously relieve the skin transport sites from continualultrasonic stress and provide increased variability in ultrasonic skintransport energy manipulation. The transducers can act in tandem,transmitting together.

[0067] The transducer array as shown in FIG. 6 provides for spreadingout drug pathway sites along the skin surface by providing ultrasonictransmission from the multiple transducer elements 61 of the arrayacting upon the skin. The transducer elements 61 may be activatedsimultaneously or sequentially to transmit ultrasound through a patchand through differing multiple sites on the skin surface, for example.Additionally, the frequency, intensity and/or waveform of an appliedsignal may be altered at each transducer element 61 within the array 60.This variation may result in increased efficiency, enhanced powerutilization and lengthening the life span of the battery of the portablesystem, for example. Additionally, alternating transducer elements 61may help keep a drug homogenized within a pocket of the transdermalpatch and help ensure that the skin is not overexposed to an excessivefrequency of ultrasound.

[0068] An array of two or more transducers, of the cymbal type forexample, may help to push drugs through multiple skin transport sites.The transducer array may further reduce skin damage and improve anefficiency and transmitted acoustical intensity. By alternating thetransducer activation sequence for example, it is possible to mitigateskin exertion and to assure greater longevity for the skin transportsites.

[0069] The application of ultrasound according to the present inventioncan be coupled with iontophoresis, the application of electric currentsapplied to the skin, in various forms of substance, or drug, delivery.Ultrasound can be applied together with iontophoresis or as apre-treatment to the application of iontophoresis, for example.Iontophoresis and/or electroporation in combination with the method andapparatus of the present invention may be used to enhance moleculartransport through the skin. According to an aspect of the presentinvention, chemical substances, such as chemical enhancers, may be usedto enhance substance transport as well.

[0070] The present invention may be used to enhance delivery of a widevariety of substances, such as medications or medicaments, nutritionalsupplements or any other suitable substance to a subject, such as ahuman patient. As described in greater detail herein below, a medicationfor example may be delivered transdermally, transcutaneously,intralumenally, and within solid tissue sites, where in all casesabsorption of the medication or a pharmacologically active portionthereof into the underlying or surrounding tissue is phonophoreticallyenhanced by the application of ultrasonic or sonic energy. Thesubstance, or medicament for example, may take any conventional form,including liquids, gels, porous reservoirs, inserts, or the like, andthe medication or pharmacologically active portion thereof may beintended to treat or alleviate an existing condition or prophylacticallyprevent or inhibit another condition of the patient. The effect of themedication may be local, such as providing for anti-tumor treatment, ormay be systemic. Suitable medicaments include broad classes of compoundsnormally delivered through the skin and other body surfaces or intosolid tissues, for example.

[0071] In general, such medications may include or incorporateanti-invectives such as antibiotics and antiviral agents; analgesics andanalgesic combinations; anorexics; antihelminthics; antiarthritics;antiasthmatic agents; anticonvulsants; antidepressants; antidiabeticagents; antidiarrheals; antihistamines; anti-inflammatory agents;antimigraine preparations; antinauseants; antineoplastics;antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics;antispasmodics; anticholinergics; sympathomimatics; xanthinederivatives; cardiovascular preparations including potassium and calciumchannel blockers, beta-blockers, and antiarrhythmics; antihypertensives;diuretics; vasodilators including general coronary, peripheral andcerebral; central nervous system stimulants; cough and coldpreparations, including decongestants; hormones such as estradiol andother steroids, including corticosteroids; hypnotics;immunosuppressives; muscle relaxants; parasympatholytics;psychostimulants; sedatives; and tranquilizers. By the method of thepresent invention, both ionized and nonionized drugs may be delivered,as can drugs of either high or low molecular weight.

[0072] Proteinaceous and polypeptide drugs represent a class of drugsbeing suitable for use in conjunction with the presently disclosedinvention. As will be evident to those possessing an ordinary skill inthe pertinent arts, such drugs cannot generally be administered orallyin that they are often destroyed in the gastrointestinal tract ormetabolized in the liver, for example. Further, due to the highmolecular weight of most polypeptide drugs, conventional transdermaldelivery systems are not generally effective.

[0073] Common examples of pharmaceutical or nutritional compounds whichmay be used with the present invention, and may be contained within atransdermal patch for example, include, but are not limited to:Acetaminophen, Antibiotics, Aspirin, Corticosterone, Erythromycin,Estradiol, Ibuprofen, Insulin, Nitroglycerin, Nicotine, Steroids such asProgesterones, Estrogens, Vitamins.

[0074] Other substances, such as pharmaceutical or nutritionalcompounds, for nutraceutical, medicinal or pharmaceutical use may alsobe utilized. It may also be desirable to use the method and apparatus ofthe invention in conjunction with substances, such as drugs, to whichthe permeability of the skin is relatively low, or which may give riseto a long lag-time. Application of ultrasound as described herein isbelieved to significantly reduce the lag-time involved with thetransdermal administration of most drugs.

[0075] Applicants have noted that many drugs may be immersed within anexcipient binder fluid, such as saline or an acetate composition, tomake them injectable. Insulin is often placed in acetate mixes forexample. By altering the excipient solution transdermal transport andthe homogenization effect within a patch pocket may be hastened andenhanced in conjunction with the application of ultrasound. Excipientsolutions high in metallic or salt content, for example, may enhance theinteraction between the drug and ultrasound. It is believed that theeffect of ultrasound at high intensity, or at low intensity butgenerating cavitation, can have a damaging effect upon many drugsubstances, such as insulin, whereupon a protein may become altered ordamaged by excessive ultrasonic or cavitation frequencies andintensities. Using an appropriate excipient carrier solution, selectedconsistently with conventional techniques for example, a substance, suchas an active drug, may mitigate damage to the substance such that itremains biofunctional after skin transport.

[0076] The following non-limiting examples are provided for purposes ofproviding a clear understanding of particular embodiments of the presentinvention.

[0077] According to an aspect of the present invention, the CymbalTransducers can be constructed as follows: the piezoelectric ceramicmaterial can take the form of a PZT4 disc 0.5-inch diameter, 1-mmthickness (PKI402) SD 0.500-0.000-0.040-402. This is available fromPiezo Kinetics Inc., Mill Road and Pine St., PO Box 756, Bellefontte Pa.16823, for example. Titanium caps can be formed of Alfa Aesar, TitaniumFoil, 0.25 mm thick, metal basis 5%, Item #10385, available from AlfaAesar, A Johnson Matthey Company 30 Bond Street, Ward Hill, Mass.01835-8099, USA.. A bonding layer material can take the form of Eccobond45 LV+catalyst 15 LV, available from Emerson & Cuming, 46 Manning Road,Billerica, Mass. 01821. Low temperature soldering material suitable foruse in connection with the Cymbal transducers include Indalloy Solder#1E, 0.30″ diameter×3 ft long, which is available from The IndiumCorporation of America 1676 Lincoln Ave., Utica, N.Y. 13502. Wires canbe formed from stranded wire, Gauge/AWG: 30, Catalog number (Digikey):A3047B-100-ND, Note: Maximum Temperature: 80C., Conductor Strand: 7/38,Voltage Range: 300V, Number of Conductors: 1, available from Alpha WireCorporation. A polymer housing can be formed of Uralite FH 3550 partA/B, available from the HB Fuller Company. Ethyl Alcohol used ispreferably about 200 proof, and fine scale sand paper can be utilized.

[0078] Referring to FIG. 4B, the titanium foil may be dye cut titaniumfoils into several disks using a circular saw having 10.7 mm diameter,for example. One side of the disks results with edges as isconventionally understood, these edges may be removed with sand paper(fine scale). An alcohol bath can then be used to remove dust generatedby sanding the disks. The disks may then be placed into a high pressure(12000 torr) shaping tool (polished side up). This step may be performedusing a custom-made punch dye in order to shape the disks into thedimensions reported in FIG. 2, for example. Resulting rough edges canagain be sanded, and the sanded disk again immersed in alcohol to removedust. The disk may be wiped to remove alcohol and dust from disk.

[0079] The thickness of the cap may be measured using a conventionaltechniques. Caps having matching or substantially matching thicknessesmay be matched together. This step may be accurate, because slightdifferences between the two caps may generate spurious resonance intothe cymbal.

[0080] The piezo disk ceramic (piezo disks) may be cleaned with alcohol.Epoxy bond may then be screen printed onto both sides of the piezo diskceramic using a process similar to T-shirt screen-printing for example.A ring of epoxy may be generated to glue the caps with the disks. Thisring may be accurate and regular in order to avoid spurious resonances.

[0081] The cymbals may then be placed on ceramic disks, and thecomposite structure placed into a press. This press may just keep thecymbal made in place, a tool where several cymbals are kept in place,for example. The pressed, compound structures may then be heated toapproximately 70° C. for four (4) hours utilizing an oven, for example.The wires may then be soldered (45) using a maximum temperature of about270° C. at the electrical contact points, 4 points per piece, forexample.

[0082] A transducer produced by the above procedure may be termed to beof a standard construction. To form a stacked construction transducer,two or more transducers 40 may be placed directly atop one another asshown in FIG. 4C and fitted together. To form an array, the transducersmay be generally connected in parallel, electrically within the polymeror epoxy bonding material as shown in FIG. 6, in either single elementform or in a stacked construction format, for example.

[0083] A series of physical tests were conducted using the singleelement cymbal transducer fabricated according to the steps outlinedabove, using standard analysis procedures common to the ultrasonic andtransducer industry. The single element transducer is a highly efficientsystem producing an ultrasonic transmission within two ranges: RANGE - ATRANSDUCER TYPE Single element “Cymbal” design FREQUENCY 20 k HzINTENSITY: LOWEST SETTING 125 mW/sq. cm. DESIGN Standard Construction

[0084] RANGE - B TRANSDUCER TYPE Single element “Cymbal” designFREQUENCY 20 k Hz INTENSITY: LOWEST SETTING 225 mW/sq. cm. DESIGNStacked Construction

[0085] Referring again to FIG. 6, a series of physical tests wereconducted using an array of cymbal transducer elements fabricatedaccording to the steps outlined above, using standard analysisprocedures common to the ultrasonic and transducer industry. The singleelement transducer is a highly efficient system producing ultrasonictransmission within two ranges: RANGE - A TRANSDUCER TYPE Single element“Cymbal” design FREQUENCY 20 k Hz INTENSITY: LOWEST SETTING 125 mW/sq.cm. DESIGN Standard Construction using nine elements

[0086] RANGE - B TRANSDUCER TYPE Single element “Cymbal” designFREQUENCY 20 k Hz INTENSITY: LOWEST SETTING 225 mW/sq. cm. DESIGNStacked Construction using nine elements

[0087] Arrays with different orientation of cymbals and withcombinations of standard and stacked arrays may be used to increaseefficiencies and to improve the effective delivery of drugs.

[0088] Alternating frequency outputs from the transducer array may beobtained. In tests, an array using nine-single elements in a standardconstruction and in a stacked construction produced frequency outputs,which could be varied from about 20 kHz to about 100 kHz. Ultrasonictransmissions were found to be most uniform at the lower frequencyrange, i.e. about 25 kHz as compared to 40, 60 or 80 kHz. Ultrasonictransmissions were found irregular at these higher frequencies. In allcases, the transducers could be made to emit responsively to a purelysinusoidal waveform or be converted to a combination waveform includingsawtooth and square waves as illustrated in FIG. 7. In these tests theultrasonic driver circuit, e.g. the frequency generator, was set topropagate 100 milliseconds of sawtooth waveform followed immediately by100 milliseconds of square waveform, before re-cycling back to sawtoothwaveform.

[0089] The transducers, whether configured in a single element or as aarray, in either a standard or stacked construction, operate using lowpower. The portable nature of the final drug delivery device, asdepicted in FIGS. 1 and 2 for example, is achieved by the presentsystem, which is worn by the patient. Accordingly, a portable powersource, such as a rechargeable battery, can be used to drive theultrasonic system. As a result, according to an aspect of theinvention: 1) low power is used to drive the transducer, from standardcommercially available battery sources for example; and, 2) longduration power, providing at least one full day of continuous power isprovided.

[0090] Tests were conducted using a nine element standard cymbal designarray set to operate at 20 k Hz frequency and at varying intensitylevels, powered by a standard “A” or “C” type battery. A useful powerlife of 25 hours was obtained at a intensity level of 200 mW/sq. cm.,with continued constant usage to the transducer array. Of course, othersuitable power sources can be used, such as “9 Volt” type batteries, forexample.

[0091] Thus, transducers used may be effectively battery powered so asto drive the ultrasonic signal, and have an efficiency of the powerutilization such that a low battery drain rate is exhibited, therebyextending the life of the power source. Accordingly a portable orwearable ultrasonic drug delivery system employing ultrasonic drugdelivery is possible utilizing conventional battery sources coupled withthe transducers which may be used according to the present invention.

[0092] The effect of the ultrasonic signal discussed in connection withthe present invention upon an active pharmaceutical substance wastested. High intensity and high frequency ultrasound may be capable ofinducing a cavitation effect within a drug, leading to an increase intemperature and a degradation of the drug molecule. Insulin (HumulinRegular-supplied by the Eli Lilly Company) was subjected to ultrasoundemitted from a stacked array of the transducers as described above, setto operate at a 20 k Hz frequency and at 125 mW/sq. cm intensity level,for one, eight and eleven continuous hours of exposure. The insulin wasplaced in a plastic pouch within a hydrophone tank containing water andstirred during ultrasonic exposure. A control sample, which wasuntreated, but allowed to sit in the pouch and tank for one, eight andeleven hours, was also made. Samples were sent for independent analysis.All samples showed no change in the insulin from the untreated insulin.

[0093]FIG. 8A shows the HPLC scan of the control sample, showing nodegradation of either the insulin or the excipient solution of theHumulin Regular sample. FIG. 8B shows the HPLC scan of theultrasonically treated eight hour sample, showing that there also was nodegradation of either the insulin or the excipient solution of theultrasonically treated Humulin Regular sample, even after eight hours ofcontinuous exposure.

[0094] Accordingly, there appears to be no damage caused to the insulinmolecule as a result of exposure to ultrasonic transmissions associatedwith the present invention (e.g. low frequency, low intensity andalternating waveform, for example).

[0095] A four-element transducer was fabricated using four standardcymbal element transducers in one array system (Array # 1) and fourstacked cymbal element transducers in another system(Array # 2). Array #1, the standard array, was set to operate at 20 k Hz frequency and at125 mW/sq. cm intensity level. Array # 2, the stacked array, was set tooperate at 20 k Hz frequency and at 225 mW/sq. cm intensity level.

[0096] The transducer arrays were fitted with a reservoir at a bottomend, into which Humulin Regular Insulin (supplied by Eli Lilly Company)was inserted. A total of 100 cc of insulin was added, providing 100units of insulin for the each test.

[0097] Ten test rats were assembled and anesthetized. The belly of therats were shaved to produce a skin area as close in configuration aswould be present in a human situation. The transducer arrays were placeddirectly onto the rat skin surface and adhered to the skin by means ofadhesive. Two groups of test rates were assembled. The first group(Group-1) were subjected to ultrasonic transmission while the secondgroup (Group-2) received no ultrasound. In the second group (Group-2),the transducers arrays were loaded with insulin and the insulin wasallowed to pool onto the surface of the rat skin, but there was noactive ultrasonic transmission.

[0098] Next a frequency generator was employed to propagate a pulsedultrasonic transmission, which used 100 millisecond pulses, with a pulserate of one pulse per second, and a duty cycle of 10%, for one hour.

[0099] Both Group-1 and Group-2 animals were tested for 120 minutes.Blood samples were taken from the animals according to standardinvestigative procedure every 30 minutes for the first hour and everyhour after and analyzed for glucose levels and the presence of insulin.The Group-1 animals were exposed to ultrasound for 60 minutes, afterwhich the ultrasound was terminated for the balance of the test period.Glucose levels in both groups were observed over the 120 minute period.

[0100]FIG. 9 illustrates the results of these tests, with an average ofthe data compiled across the number of tests conducted. Specificallythis data relates the average Glucose level of the Group-1 animalstreated with ultrasound and the Group-2 animals, which were untreated,but where the insulin was placed in a blank array (containing notransducers) and placed upon the skin surface. At minute 0, before theultrasound was activated, both groups had similar starting glucoselevels. At minute 30 and minute 60 the Group-1 animals showed asignificant reduction in glucose levels while the Group-2 animals showedno lowering in glucose level. At minute 60, the ultrasound wasterminated and the animals monitored for another 60 minute period. TheGroup-2 animals showed no decrease in glucose levels, as the insulin wasnot absorbed through the skin. The Group-1 animals, which had a loweringof their glucose levels during active ultrasound transmission,indicating that the ultrasound enabled the permeation of the insulinthrough the skin, were observed to have a rise in their glucose levelsupon termination of the ultrasound.

[0101] At minute-120 the Group-2 animals showed no decrease while theGroup-1 animals showed their glucose levels to be rising to the previouspre-ultrasound levels. This test showed that the insulin was onlypermeated through the skin via the ultrasound emitted from thetransducer arrays, and only with the presence of active ultrasound. Thetests also confirmed that insulin, placed on the skin or delivered via atransdermal patch did not permeate through the skin on its own. Thesetests also confirm the validity of the transducer designs describedherein as an effective means for delivering ultrasonically enhancedtransdermal drug delivery.

[0102] These tests also showed that insulin delivered transdermally bythe portable transducers can effectively decrease glucose levels. Thisresult showed that the insulin is not only absorbed through the stratumcorneum but it is also absorbed into the blood stream in an effectiveform and can cause its metabolic effect of lowering glucose.

[0103] Examination of the skin features of the tested rats showed nodamage to the skin surface, no discoloration or abnormal fractures afterthe application of ultrasound emitted from the transducers.

[0104] The device of this invention provides certain drug deliveryfunctions, including but not limited to: non-invasive drug deliverythrough the use of ultrasound applied transdermally to a patient's skinsurface; penetration/absorption enhancement through the skin so thatmedicines contained within a transdermal patch become more readilyabsorbed through the skin layers into a patient's blood stream;homogenization and droplet size reduction of pharmaceutical agentscontained within a transdermal patch, to make the resultingultrasonically treated drug more readily absorbable through a patient'sskin layers. The method and apparatus of the present invention may beespecially well suited for difficult to administer drugs such as insulinand various hormone medicines; the device may go with the patient, to bewearable by the patient, and use rechargeable batteries to providetreatment mobility.

[0105] Some elements of this invention also worthy of noting include,but are not limited to: (a) The ability to provide a portable andwearable ultrasonic drug delivery device which goes with the patient.(b) The use of drug delivery pathway which includes hair follicle andskin pore delivery as opposed to breaching the stratum corneum. The drugcontained within the drug pocket of the transdermal patch may ultimatelypenetrate into the patient's blood stream, aided by the sonictransmission through the skin pores or hair follicles and into themuscular of the patient. This pathway approach may reduce the chance ofdamaging the skin and enables the use of lower ultrasonic frequenciesand intensities. (c) The use of a transducer array, which enablesultrasonic skin transport at more than one site on the skin, which mayprovide a greater chance of effective skin transport and avoidovertaxing just one delivery site. The use of multiple transducers mayoffer varied treatment effects to facilitate maximum skin transport ofthe target active pharmaceutical agent, by providing tandem drugtransport across multiple transducer elements, by enabling sequencing ofthe transducer elements in the array, whereupon the transducers may actat different frequencies and intensity levels of ultrasound. (d) Usingan array of transducers in a portable, wearable ultrasonic drug deliverydevice, especially utilizing cymbal type transducers, may provide higherpower utilization efficiencies and helps to avoid the damaging effectsof excessive cavitation upon the skin. Using an array may help enablelong duration battery supplies providing sufficient power to enable theapparatus to function for several days between recharge or replacementcycles. The use of a rechargeable battery supply, with batteriescontained with the strap of the device for example, may afford totalmobility for the patient and a reliable power supply for the device overseveral months of recycled use, for example. (e) Applicants further notethat the use of transmission in both the sonic and ultrasonic ranges maybe combined to achieve optimal transport through the skin or mucosalmembranes. (f) To deliver the proper dose of a drug across the skin, inminutes as opposed to the hours noted in the previous art. (g) The useof low frequency ultrasound, from about 20 k Hz-about 100 kHz, with analternating waveform (from sawtooth to square wave for example), withcymbal type transducers, may enable battery powered ultrasonictransmission. Further, a transducer array may help to avoid overexerting a single skin transport site and providing versatility inultrasonic frequency and intensity ranges per transducer element.

[0106] Having described the invention in the above detail, those skilledin the art will recognize that there are a number of variations to thedesign and functionality for the device, but such variations of thedesign and functionality are intended to fall within the presentdisclosure. Further, although the invention has been disclosed with acertain degree of particularity, it is understood that the presentdisclosure of the preferred forms has been made by way of example, andthat numerous changes in the details of construction and combination andarrangement of parts and steps may be made without departing from thespirit and scope of the invention as hereinafter claimed.

What is claimed is:
 1. A method for enhancing delivery of at least onesubstance through a surface of and into a subject, said methodcomprising: placing at least one ultrasonic signal emitting deviceadjacent to said at least one substance and to said subject; and,applying at least one alternating ultrasonic signal to said at least onesubstance using said ultrasonic signal emitting device so as to effectmovement of at least a portion of said substance through said surfaceand into said subject.
 2. A method for enhancing delivery of at leastone substance through a surface of and into a living subject, saidmethod comprising: placing at least one ultrasonic signal emittingdevice adjacent to said at least one substance and to said subject; and,applying at least one ultrasonic signal to said at least substance usingsaid ultrasonic signal emitting device so as to effect movement of atleast a portion of said substance through said surface and into saidsubject; wherein, said at least one ultrasonic signal includes at leasta square waveform portion and a sawtooth waveform portion.